Traditionally, drug delivery systems have focused on constant/sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and reduce adverse effects. Reduced dosing frequency and improved patient compliance can also be expected for constant/sustained release drug delivery systems, compared to immediate release preparations. However, for certain drugs, sustained release delivery is not suitable and is affected by the following factors:
First pass metabolism: Some drugs, such as β-blockers, β-estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability.
Biological tolerance: Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin.
Chronopharmacology and circadian rhythms: Circadian rhythms in certain physiological functions are well established. It has been recognized that a symptom or disease onset can occur during specific time periods of the 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours (Lemmer, B, J Controlled Release. 1991; 16:63-74; Lemmer B, Pulsatile Drug Delivery: Current Applications and Future Trends (R Gurney, H E Junginger, N A Peppeas, eds.) 1993; 11-24).
Local therapeutic need: For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.
Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.
Drug absorption differences in various gastrointestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery system to pump out the drug much faster when the system reaches the distal segment of the intestine, to avoid the entombment of the drug in the feces.
Pulsed dose delivery systems, prepared as either single unit or multiple unit formulations, and which are capable of releasing the drug after a predetermined time, have been studied to address the aforementioned problematic areas for sustained release preparations. These same factors are also problematic in pulsed dose formulation development. For example, gastrointestinal transit times vary not only from patient to patient but also within patients as a result of food intake, stress, and illness; thus a single-unit pulsed-release system may exhibit higher variability compared to a multiple unit system. Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-to-optimize process. Particularly challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile formulation development, i.e., lag time and rapid release.
Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and the EUDRAGIT® acrylic polymers, have been used as gastroresistant, enterosoluble coatings for single drug pulse release in the intestine (Xu X and Lee P, Pharm Res. 1993; 10(8):1144-1152). The enteric materials, which are soluble at higher pH values, are frequently used for colon-specific delivery systems. Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as inter- and intra-subject variability are major issues for using enteric coated systems as a time-controlled release of drugs.
A retarding, swellable hydrophilic coating has been used for oral delayed release systems (Gazzaniga et al., Eur J Pharm Biopharm. 1994; 40(4):246-250; Gazzaniga et al., S.T.P. Pharma Sciences. 1996; 5(1):83-88). It was demonstrated that lag time was linearly correlated with coating weight gain and drug release was pH independent.
Hydroxypropyl methylcellulose barriers with erodible and/or gellable characteristics formed using press coating technology for tablet dosage forms have been described to achieve time-programmed release of drugs (Conte et al., Biomaterials. 1993; 14(13):1017-1023). Barrier formulation variables (such as grade of hydroxypropyl methylcellulose, water-soluble and water-insoluble excipients) significantly altered the lag time and the release rate from the center cores.
Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE® 60SH, 90SH (Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow Chemical Company, USA) have been used as a hydrophilic matrix material to achieve bimodal drug release for several drugs, i.e., aspirin, ibuprofen, and adinazolam (WO 87/00044). Bimodal release is characterized by a rapid initial release, followed by a period of constant release, and then by a second rapid drug release.
Tablets or capsules coated with a hydrophobic wax-surfactant layer, made from an aqueous dispersion of carnauba wax, beeswax, polyoxyethylene sorbitan monooleate, and hydroxypropyl methylcellulose have been used for rapid drug release after a predetermined lag time. However, even though a two-hour lag time was achieved for the model drug theophylline at a higher coating level (60%), three hours were required for a complete release of theophylline after the lag time. (Walia et al., Pharm Dev Tech. 1998; 3(1):103-113)
A sustained-release drug delivery system is described in U.S. Pat. No. 4,871,549. When this system is placed into dissolution medium or the gastrointestinal tract, water influx and the volume expansion of the swelling agent cause the explosion of the water permeable membrane. The drug thus releases after a predetermined time period.
The OROS® push-pull system (Alza Company) has been developed for pulsatile delivery of water-soluble and water-insoluble drugs (Theeuwes, Drug Dev Ind Pharm. 1983; 9(7):1331-1357; Theeuwes F, Novel Drug Delivery and Its Therapeutic Application (LF Prescott and WS Nimmos eds.) 1989; 323-340), e.g. the OROS-CT® system and is based on the swelling properties of an osmotic core compartment which provides a pH-independent, time-controlled drug release.
The PULSINCAP® dosage form releases its drug content at either a predetermined time or at a specific site (e.g., colon) in the gastrointestinal tract (WO 90/09168). The drug formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the PULSINCAP® dosage form and the encapsulated drug is released. A pulsatile capsule system containing captopril with release after a nominal 5-hr period was found to perform, reproducible in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine. (Wilding et al., Pharm Res. 1992; 9(5):654-657)
ADDERALL® is an immediate release composition, which includes a mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate. This combination of amphetamines is indicated for the treatment of Attention Deficit Hyperactivity Disorder in children from 3-10 years of age.
One disadvantage of immediate release-only treatments for children is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision. This requires a second treatment, which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing tablet formulations. ADDERALL XR® met the need for a dosage form, which can be administered once, in place of the two oral doses which are needed using the conventional drug delivery formulations of the prior art. See U.S. Pat. Nos. 6,322,819 and 6,605,300; co-pending Reissue Application Nos. 11/091,010 and 11/091,011.
There are currently two medications (ADDERALL XR® and STRATTERA™) approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD in adults. ADDERALL XR® is a mixed amphetamine salts medication. STRATTERA™ is an atomoxetine (a norepinephrine reuptake inhibitor) medication. Long acting stimulant preparations, such as ADDERALL XR® and CONCERTA® (methylphenidate), are designed to provide a duration of effect up to 12 hours. However, clinicians have noted that a proportion of patients treated with these formulations require additional treatment with a short-acting stimulant to extend the daily therapeutic effect. For patients taking long-acting stimulant formulations who require duration of clinical benefit beyond 10-12 hours, clinicians have augmented the morning long-acting formulation, typically at 8-10 hours post-dose, with a dose of the same immediate-release (IR) medication. Typically, the dose of the IR medication is smaller than the long-acting dose. This augmentation strategy is most relevant to the “longer day demands” of adult and adolescents, rather than school age, pediatric patients.
Thus, a need exists for a once-daily, long-acting oral composition that provides effective treatment of ADHD, without supplementation, for patients with longer day demands (e.g., 14-16 awake hours).